Zhen-Yu He

Predictive value of breast cancer molecular subtypes in Chinese patients with four or more positive nodes after postmastectomy radiotherapy.

The molecular subtypes of breast cancer based on status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) expression are associated with markedly different clinical outcomes. We retrospectively analyzed 774 breast cancer patients with four or more positive nodes, who underwent mastectomy between March 1999 and December 2007. Treatment with postmastectomy radiotherapy (PMRT) reduced the rates of locoregional recurrence-free survival (LRFS; 6.7% vs. 26.6%), distant metastasis-free survival (DMFS; 26.9% vs. 50.0%), and mortality (24.4% vs. 45.3%) for luminal-A subtypes (ER+ or PR+, Her2-) and reduced LRFS (12.1% vs. 27.5%) for the luminal-B subtype (ER+ or PR+, Her2+) compared with patients not receiving PMRT. However, PMRT did not affect the endpoints for the Her2-enriched or basal subtypes. Thus, understanding the differences in patterns of relapse between the different subtypes of breast cancer may enable targeted adjuvant therapy and improved surveillance decisions.

Prognostic Value of Ki-67 in Breast Cancer Patients with Positive Axillary Lymph Nodes: A Retrospective Cohort Study

Introduction Ki-67 expression is a biomarker for proliferation. Its prognostic value is recognized in breast cancer (BC) patients with negative axillary nodes, but is less clear in BC patients with positive axillary lymph nodes. Methods We retrospectively reviewed the medical records of 1131 Chinese BC patients treated from January 2002 to June 2007 and 450 patients met the inclusion criteria: positive nodes, adjuvant therapy, and complete biomarker profile (estrogen receptor (ER), progesterone receptor (PR), HER2, p53, Ki-67). Univariate and multivariate regression analysis were used to correlate biomarkers and tumor characteristics with metastasis free survival (MFS) and overall survival (OS). Results Median follow-up time was 46 months (range 5–76 months). The Ki-67 expression was associated significantly with histological grade, ER, PR, HER2, and P53 status (P<0.05). Tumor stage, nodal stage, and ER status were independent prognostic factors for MFS. Ki-67 status was associated significantly with OS but not MFS. To determine whether the extent of LN involvement in the BC patients influenced the role of Ki-67 in survival rates, we compared these variables in patients with 1–3 positive lymph nodes (N1) to those of patients with ≥4 positive lymph nodes. Ki-67 status was an independent prognostic factor for MFS (Hazard Ratio, 3.27, P = 0.026) and overall survival (HR, 10.64, P = 0.007) in patients with 1–3 positive nodes (N1). Conclusions The possibility that Ki-67 expression together with clinical factors can improve prediction of the prognosis of BC patients with 1∼3 positive axillary lymph nodes warrants further studies.

The Activation of ERK1/2 and JNK MAPK Signaling by Insulin/IGF-1 Is Responsible for the Development of Colon Cancer with Type 2 Diabetes Mellitus

Previous studies showed that type 2 diabetes mellitus (T2DM) is linked to increased risk of developing colon cancer. Insulin and insulin-like growth factor 1 (IGF-1) are increased in patients with T2DM. The increased insulin and IGF-1 may be responsible for the developing of colon cancer. In this study, we investigated the effects and mechanisms of insulin and IGF-1 in colon cancer development in vitro and in vivo. Insulin and IGF-1 alone or together elevated proliferation and reduced apoptosis in colon cancer MC38 cells. Meanwhile, insulin and IGF-1 promoted the phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Treatment with ERK1/2 or JNK inhibitor in the presence of insulin and IGF-1 significantly decreased B-cell lymphoma 2 (Bcl-2) and increased Bcl-2-associated X protein (Bax) expression and finally increased apoptosis and inhibited the proliferation. Accelerative colon tumor growth was found in a mouse model of T2DM with db/db mice which got high level of endogenous insulin and IGF-1. Furthermore, the inhibition of ERK1/2 or JNK suppressed the development of colon tumor in vivo. These results suggest that the activation of ERK1/2 and JNK signaling by insulin and IGF-1, at least in part, is responsible for the development of colon cancer with T2DM.

Thymosin beta 10 is a key regulator of tumorigenesis and metastasis and a novel serum marker in breast cancer

BackgroundThymosin beta 10 (TMSB10) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to determine the biological roles and clinical significance of TMSB10 in breast cancer and to identify whether TMSB10 might be used as a serum marker for the diagnosis of breast cancer.MethodsTMSB10 expression was evaluated by immunohistochemical analysis (IHC) of 253 breast tumors and ELISA of serum from 80 patients with breast cancer. Statistical analysis was performed to explore the correlation between TMSB10 expression and clinicopathological features in breast cancer. Univariate and multivariate Cox regression analysis were performed to examine the association between TMSB10 expression and overall survival and metastatic status. In vitro and in vivo assays were performed to assess the biological roles of TMSB10 in breast cancer. Western blotting and luciferase assays were examined to identify the underlying pathway involved in the tumor-promoting role of TMSB10.ResultsWe found TMSB10 was upregulated in breast cancer cells and tissues. Univariate and multivariate analysis demonstrated that high TMSB10 expression significantly correlated with clinicopathological features, poor prognosis and distant metastases in patients with breast cancer. Overexpression of TMSB10 promotes, while silencing of TMSB10 inhibits, proliferation, invasion and migration of breast cancer cells in vitro and in vivo. Our results further reveal that TMSB10 promotes the proliferation, invasion and migration of breast cancer cells via AKT/FOXO signaling, which is antagonized by the AKT kinase inhibitor perifosine. Importantly, the expression of TMSB10 is significantly elevated in the serum of patients with breast cancer and is positively associated with clinical stages of breast cancer.ConclusionTMSB10 may hold promise as a minimally invasive serum cancer biomarker for the diagnosis of breast cancer and a potential therapeutic target which will facilitate the development of a novel therapeutic strategy against breast cancer.

Dosimetric Comparison of the Simultaneous Integrated Boost in Whole-Breast Irradiation after Breast-Conserving Surgery: IMRT, IMRT plus an Electron Boost and VMAT

Objectives To compare the target volume coverage and doses to organs at risks (OARs) using three techniques that simultaneous integrated boost (SIB) in whole-breast irradiation (WBI) after breast-conserving surgery, including intensity-modulated radiation therapy (IMRT), IMRT plus an electron boost (IMRT-EB), and volumetric-modulated arc therapy (VMAT). Methods A total of 10 patients with early-stage left-sided breast cancer after breast-conserving surgery were included in this study. IMRT, IMRT-EB and VMAT plans were generated for each patient. Results The conformity index (CI) of the planning target volumes evaluation (PTV-Eval) of VMAT was significantly superior to those of IMRT and IMRT-EB (P < 0.05). The CI of the PTV Eval-boost of VMAT was better than that of IMRT (P = 0.018) and IMRT-EB (P < 0.001), while the CI of the PTV Eval-boost of IMRT was better than that of IMRT-EB (P = 0.002). The V5, V10 and Dmean in ipsilateral lung with VMAT were significantly higher than IMRT (P < 0.05) and IMRT-EB (P < 0.05). The Dmean, V5 and V10 in heart with VMAT were significantly greater than those of IMRT and IMRT-EB (P < 0.05). There was no significant difference in the OARs between IMRT and IMRT-EB (P > 0.05). Conclusions Considered the target volume coverage and radiation dose delivered to the OARs (especially the heart and lung), IMRT may be more suitable for the SIB in WBI than IMRT-EB and VMAT. Additional clinical studies with a larger sample size will be needed to assess the long-term feasibility and efficacy of SIB using different radiotherapy techniques.

Use of the Metastatic Lymph Node Ratio to Evaluate the Prognosis of Esophageal Cancer Patients with Node Metastasis Following Radical Esophagectomy

Objectives The objective of this study was to investigate the number of metastatic lymph nodes (pN) and the metastatic lymph node ratio (MLR) on the post-surgical prognosis of Chinese patients with esophageal cancer (EC) and lymph node metastasis. Methods We enrolled 353 patients who received primary curative resection for EC from 1990 to 2003. The association of pN and MLR with 5-year overall survival (OS) was examined by receiver operating characteristic (ROC) and area under the curve (AUC) analysis. The Kaplan-Meier method was used to calculate survival rates, and survival curves were compared with the log-rank test. The Cox model was employed for univariate and multivariate analyses of factors associated with 5-year OS. Results The median follow-up time was 41 months, and the 1-, 3- and 5-year OS rates were 71.2%, 30.4%, and 19.5%, respectively. Univariate analysis showed that age, pN stage, and the MLR were prognostic factors for OS. Patients with MLRs less than 0.15, MLRs of 0.15-0.30, and MLRs greater than 0.30 had 5-year OS rates of 30.1%, 17.8%, and 9.5%, respectively (p < 0.001). Patients classified as pN1, pN2, and pN3 had 5-year OS rates of 23.7%, 11.4%, and 9.9%, respectively (p < 0.001). Multivariate analysis indicated that a high MLR and advanced age were significant and independent risk factors for poor OS. Patients classified as pN2 had significantly worse OS than those classified as pN1 (p = 0.022), but those classified as pN3 had similar OS as those classified as pN1 (p = 0.166). ROC analysis indicated that MLR (AUC = 0.585, p = 0.016) had better predictive value than pN (AUC = 0.565, p = 0.068). Conclusions The integrated use of MLR and pN may be suitable for evaluation of OS in Chinese patients with EC and positive nodal metastasis after curative resection.

A novel prognostic score model incorporating CDGSH iron sulfur domain2 (CISD2) predicts risk of disease progression in laryngeal squamous cell carcinoma

Background The role of CDGSH iron sulfur domain 2 (CISD2) in laryngeal squamous cell carcinoma (LSCC) remains unclear. Results CISD2 were up-regulated in LSCC tissues compared with adjacent noncancerous tissues both at mRNA and protein levels. CISD2 was significantly correlated with T stage, lymph node metastasis, clinical stage and disease progression. A prognostic model (C-N model) for PFS was subsequently constructed based on independent prognostic factors including CISD2 and N classification. This model significantly divided LSCC patients into three risk subgroups and was more accurate than the prediction efficacy of TNM classification in the training cohort (C-index, 0.710 vs 0.602, P = 0.027) and validation cohort (C-index, 0.719 vs 0.578, P = 0.014). Methods Real-time PCR and Western blotting were employed to examine the expression of CISD2 in eight fresh paired LSCC samples. Immunohistochemistry was performed to assess CISD2 expression in 490 paraffin-embedded archived LSCC samples. A prognostic model for progression-free survival (PFS) was built using independent factors. The concordance index (C-Index) was used to evaluate the prognostic ability of the model. Conclusions CISD2 was up-regulated in LSCC. The novel C-N model, which includes CISD2 levels and N classification, is more accurate than conventional TNM classification for predicting PFS in LSCC.

Correction: Postmastectomy Radiotherapy Improves Disease-Free Survival of High Risk of Locoregional Recurrence Breast Cancer Patients with T1-2 and 1 to 3 Positive Nodes

Objectives The indications for post-mastectomy radiotherapy (PMRT) with T1-2 breast cancer and 1-3 positive axillary lymph nodes is still controversial. The purpose of this study was to investigate the role of PMRT in T1-2 breast cancer with 1-3 positive axillary lymph node. Methods We retrospectively reviewed the file records of 79 patients receiving PMRT and not receiving PMRT (618 patients). Results The median follow-up was 65 months. Multivariate analysis showed that PMRT was an independent prognostic factor of locoregional recurrence-free survival (LRFS) (P = 0.010). Subgroup analysis of patients who did not undergo PMRT showed that pT stage, number of positive axillary lymph nodes, and molecular subtype were independent prognostic factors of LRFS. PMRT improved LRFS in the entire group (P = 0.005), but did not affect distant metastasis-free survival (DMFS) (P = 0.494), disease-free survival (DFS) (P = 0.215), and overall survival (OS) (P = 0.645). For patients without PMRT, the 5-year LRFS of low-risk patients (0–1 risk factor for locoregional recurrence) of 94.5% was significantly higher than that of high-risk patients (2-3 risk factors for locoregional recurrence) (80.9%, P < 0.001). PMRT improved LRFS (P = 0.001) and DFS (P = 0.027) in high-risk patients, but did not improve LRFS, DMFS, DFS, and OS in low-risk patients. Conclusions PMRT is beneficial in patients with high risk of locoregional recurrence breast cancer patients with T1-2 and 1 to 3 positive nodes.

Second-line combination chemotherapy with vinorelbine and capecitabine in patients with advanced breast cancer previously treated with anthracyclines and/or taxanes.

Objective: This phase II study was designed to evaluate the effects of vinorelbine (VRL) and capecitabine (CAP) as second-line combination chemotherapy in patients with advanced breast cancer (ABC) previously treated with anthracyclines and/or taxanes. Methods: Treatment consisted of VRL 25 mg/m2 administered on days 1 and 8 of a 21-day treatment cycle, along with oral CAP 825 mg/m2 twice daily for 14 days, followed by 7 days of rest. Results: 50 patients were enrolled and 48/50 (96.0%) patients were assessable for response. The median time to progression (TTP) and overall survival (OS) of the patients were 5.0 (95% confidence interval, CI, 2.1–7.9 months) and 12.0 months (95% CI, 8.0–16.0 months), respectively. The objective response rate was 26.0% (95% CI, 13.8–38.2%) with 1 confirmed complete response and 12 partial responses. The most frequent hematological adverse event was neutropenia of grade 3 and 4 in 5 (10.4%) and 2 patients (4.2%), respectively. Grade 3 stomatitis, asthenia, and diarrhea were observed in 1 (2.1%), 2 (4.2%) and 3 (6.3%) patients, respectively. Conclusion: The combination of VRL and CAP is feasible as second-line chemotherapy in patients with ABC previously treated with anthracyclines and/or taxanes, with efficacy being comparable to other available combination regimens.

Downregulation of hsa_circ_0011946 suppresses the migration and invasion of the breast cancer cell line MCF-7 by targeting RFC3

Introduction Although some circRNAs have been found to regulate the progression of malignancies, their functions and coupled molecular mechanisms are still unclear. In our study, we sought to assess the underlying molecular mechanisms of circRNAs in breast cancer and therefore explored the differentially expressed circRNAs and co-expression networks, followed by in vitro experiments. Materials and methods High-throughput RNA sequencing was performed to obtain an unbiased profile of circRNA expression. CircRNA-miRNA-mRNA co-expression networks were predicted, and sequence analyses were carried out. The MTT, transwell migration and invasion assay was conducted in Michigan Cancer Foundation-7 cells that had been transfected with si-circRNA and si-negative control (si-NC). Results A total of 152 circRNAs were differentially expressed in breast cancer tissues, among which 85 were upregulated and 67 downregulated. Out of these, hsa_circ_0011946 was selected and the subsequent bioinformatics analysis predicted that hsa_circ_0011946 sponging miR-26a/b directly targeted replication factor C subunit 3 (RFC3) and that its knockdown could inhibit RFC3 mRNA and protein expression. Furthermore, hsa_circ_0011946 loss-of-function significantly suppressed the migration and invasion of Michigan Cancer Foundation-7 cells. Conclusion Together, these results indicate that hsa_circ_0011946 and RFC3 comprise a novel pathway involved in the progression of breast cancer.